Rotigotine ((S)-(−)-5-hydroxy-2-(N-n-propyl-N-2-thienylethyl)-aminotetralin) is represented by the following structural formula:

Rotigotine is a non-ergolinic dopamine-receptor agonist, which is used for the treatment of the signs and symptoms of early-stage idiopathic Parkinson's disease. The drug is administered via a silicon-based transdermal delivery patch.
Rotigotine is sold in Europe by Schwarz Pharma as NEUPRO® and was recently approved by the FDA for use in the U.S. NEUPRO® is formulated as 10 cm2, 20 cm2, 30 cm2, and 40 cm2 transdermal patches containing 4.5 mg, 9.0 mg, 13.5 mg and 18.0 mg rotigotine per base, respectively, designed to release 2 mg, 4 mg, 6 mg and 8 mg, respectively, of rotigotine per 24 hours.
The preparation of racemic rotigotine hydrochloride is disclosed in U.S. Pat. No. 4,564,628. The process, which is depicted in Scheme 1, comprises reacting 5-methoxy-2-tetralone (Compound I) with β-(2-thienyl)ethylamine in presence of p-toluenesulfonic acid and sodium cyanoborohydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-[2-(thienyl)-ethyl]-2-naphthaleneamine (Compound II), which is reacted with propionyl chloride in presence of triethylamine to obtain N-(1,2,3,4-tetrahydro-5-methoxy-2-naphthenyl)-N-[2-(2-thienyl)ethyl)]propaneamide (Compound III). This propanamide is reduced with lithium aluminum hydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (Compound IV), which is subsequently reacted with boron tribromide, then hydrochloric acid (HCl) to form the racemic rotigotine hydrochloride (Compound V).

Another process for preparing racemic rotigotine hydrochloride, which is disclosed in U.S. Pat. No. 4,564,628, is shown in Scheme 2 below. 5-methoxy-2-tetralon (Compound I) is reacted with 3-propylamine in acetic acid and H2/PtO2 to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthaleneamine (Compound VI). This intermediate then is reacted either with 2-thienylacetic acid in presence of borane trimethylamine complex in xylene or with 2-thienylacetyl chloride and lithium aluminum hydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (Compound IV). Finally, this intermediate is reacted with boron tribromide, then with HCl, to form the racemic rotigotine hydrochloride (Compound V).

U.S. Pat. No. 4,885,308 discloses a process for obtaining the two optical isomers of rotigotine by resolving the racemic 2-(N-n-propylamino)-5-methoxytetralin to its two enantiomers, then converting each enantiomer to (+) and (−)-rotigotine, using the process disclosed in U.S. Pat. No. 4,564,628.
The last step in the synthesis of rotigotine, as recited in several patents, such as U.S. Pat. Nos. 4,564,628 and 6,372,920, involves the direct formation of the hydrochloride salt of rotigotine. For instance, none of the five examples of U.S. Pat. No. 6,372,920 detail how the formation of the rotigotine hydrochloride salt is carried out, it is only mentioned that “rotigotine base is converted to its hydrochloride salt form in the usual manner.” Example II of U.S. Pat. No. 4,546,628 discloses that the free base of rotigotine is obtained by evaporating a solution of rotigotine to dryness, but the resulting residue was immediately converted to the hydrochloride salt (without isolation). This HCl salt was characterized and reported to have a melting point of 148-150° C.
Although U.S. Pat. Nos. 4,564,628 and 4,885,308 disclose the formation of the free base of rotigotine, using these disclosed procedures results in an oil, not in a more desirable solid form, implying that it is difficult to obtain a crystalline rotigotine base.
According to US Patent Application No. 2004/0048779, rotigotine hydrochloride is converted into rotigotine free base by treating rotigotine hydrochloride with sodium metasilicate or sodium trisilicate for 48 hours, or by treating rotigotine hydrochloride with sodium hydroxide (NaOH) followed by addition of sodium phosphate buffer solution, as disclosed in Examples 3 and 4, respectively. Thus, the preparation of rotigotine base is in situ, the product is not isolated, and its physical properties have not been reported to in these patents or patent publications. On the basis of the above mentioned data, it may be concluded that the previously reported means of synthesizing rotigotine are insufficient for isolating, purifying, and preparing a stable form of the rotigotine base suitable for handling and storing.
Because a transdermal delivery patch contains rotigotine base as opposed to rotigotine hydrochloride, a need exists for a solid rotigotine base, preferably in a crystalline form, that can be used as the active material in transdermal delivery patches.